Reactions to injury and infection [inflammation, fever and changes collectively called the acute phase response (APR)] are mediated via cytokines produced within the host. There is increasing evidence that neuropeptides act as messengers among the central nervous, immune and endocrine systems to influence host defense. Previous research on this project suggests that cytokines evoke release of the neuropeptide alpha-MSH, a molecule that in turn modulates cytokine activity both within the CNS and peripherally, and it is this model of peptide/cytokine relations that forms the theoretical framework of the proposed project. This modulatory property of alpha-MSH may have clinical implications, but much remains to be learned before clinical use is possible. First, it is important to learn whether specific cytokines, including IL-1beta and TNFalpha, release alpha-MSH and activate particular components of the APR and to determine if alpha-MSH modulates these host defense responses. It is then important to understanding of control of the APR to determine if small amino acid ("message") sequences of alpha-MSH, given centrally or peripherally, can influence specific aspects of the cytokine-induced APR. A major aim is to learn if peripheral inflammation, which is inhibited by peripheral alpha-MSH, is also inhibited when the peptide is given centrally. A correlation between circulating cytokine and alpha-MSH concentrations during arthritic inflammation, suggested by pilot data, will likewise be examined in a prospective study. The plan includes experiments to determine if antipyretic and anti-inflammatory drugs act by increasing the concentration of alpha-MSH in the circulation. Related experiments will test the hypothesis that alpha-MSH peptides inhibit neutrophil migration into sites of inflammation induced by cytokines; the results may elucidate one mechanism of action of alpha-MSH. Increased circulating alpha-MSH in endotoxemia, noted in pilot research, suggests that alpha-MSH is normally released after endotoxin induces cytokine production. If so, then administration of exogenous alpha-MSH may modulate such cytokine activity and improve survival in septic shock. A general aim is to learn how the concentrations and activities of specific cytokines and alpha-MSH are related in a live animal model that shares host defense mechanisms with man. The results will improve understanding of relations between cytokines and neuropeptide modulation; the knowledge may have clinical implications that parallel the ubiquitous activities of the cytokines.